Neuromuscular I

Neuromuscular System I

• This is a lecture on the neuromuscular system, part of a course called Applied Physiology (PT 8202).
• The objectives include membrane potentials, action potentials, skeletal muscle structure, and skeletal muscle contraction.

Objectives

• Membrane potentials and action potentials are crucial for nerve and muscle function.
• Skeletal muscle structure and function are addressed, explaining the organization of muscle tissue from the whole muscle to individual muscle fibers.

Neuromuscular Domains

• Motor units, fiber types, and EC coupling are related to neuromuscular structure and function.
• Neuromuscular health/function and force generation interplay.
• Bioenergetic and signaling properties of muscles are also discussed.

Membrane Potentials and Action Potentials

• Net diffusion rate depends on membrane permeability, concentration gradient, electrical potential gradient, and pressure gradient, with electrical and concentration forces working at varying rates.
• Electrical potentials exist across cell membranes.
• These impulses transmit signals along nerves and muscles.
• The Nernst potential is the potential difference that opposes net ion diffusion through a membrane. Magnitude relates to ion concentration ratios on each side of the membrane.

Diffusion Potentials

• Membrane potentials are caused by ion differences (concentration gradients) across selectively permeable membranes.
• Potassium is more concentrated inside nerve cells.
• Sodium is more concentrated outside nerve cells.
• These differences are key determinants of the resting membrane potential.

Diffusion Potentials - K+

• Potassium ions tend to diffuse out of nerve cells due to their concentration gradient.
• The outward flow of positive ions creates a negative potential inside the nerve fiber (-94 millivolts).

Diffusion Potentials - Na+

• Sodium ions tend to diffuse into nerve cells due to their concentration gradient.
• The inward flow of positive ions creates a positive potential inside the nerve fiber (+61 millivolts).

Resting Membrane Potential

• The resting membrane potential is the electrical potential difference across the membrane of a nerve cell when it is at rest.
• It depends on the concentration difference of ions across the membrane.
• It is stabilized in dormancy by various channels & transporters that affect ion movement.
• The permeability of different ion types is crucial in regulating the resting membrane potential. Specific ion permeabilities, such as potassium permeability, impact resting membrane values.
• Various cell types have different resting membrane potentials. For example, skeletal muscle fibers have resting potentials between -85 to -95 mV.

Resting membrane potential

• The resting membrane potential's stabilization involves potassium diffusion, sodium diffusion, sodium-potassium pumps, and contributions from chloride ions, with each playing a role in the membrane potential balance.
• There are more potassium leak channels (100x) than sodium leak channels.
• The sodium-potassium pump maintains the concentration gradient by pumping more sodium ions out of the cell than potassium ions into the cell.

Action Potentials

• Rapid changes in membrane potential that propagate along nerve fibers.
• Each action potential starts with a sudden change from resting negative potential, transitions to a positive potential then rapidly returns to negative potential.
• This triggers a series of similar changes in adjacent areas, propagating the signal.
• Depolarization leads to the opening of voltage-gated sodium and potassium channels.
• Action potentials are all-or-nothing events.
• The action potential's generation relies on exceeding a particular threshold voltage.

Action Potentials Stages

• Resting stage, depolarization stage, repolarization stage, and hyperpolarization stage occur in sequences as a result of sodium and potassium channel dynamics.
• The permeability for sodium rapidly increases, and then for potassium.
• This interplay between sodium and potassium channels is key in defining and sustaining electrical signals.
• Voltage-gated sodium and potassium channels are critical in the process of depolarization and repolarization during action potentials.

Refractory Period

• A refractory period is a time period after an action potential during which it is difficult or impossible to fire another one, limiting the frequency of action potentials. This is due to inactivation of sodium channels, and the reestablishment of the resting potential.

Signal Transmission

• Saltatory conduction is a mechanism of signal transmission in myelinated nerve fibers.
• Schwann cells produce myelin sheaths around nerve fibers.
• Myelin sheaths speed up signal transmission, leaping from node to node.

Saltatory Conduction

• Action potentials are propagated from node to node in myelinated nerve fibers.
• This allows for faster conduction velocity (5 to 50-fold) compared to non-myelinated nerve fibers.
• Energy is conserved because depolarization events do not occur along every point of the neuron.

Conduction Velocity

• Myelinated axons have faster conduction velocities compared to non-myelinated axons.
• This difference impacts the speed of nerve impulses.

Clinical Application – Multiple Sclerosis

• MS is an immune-mediated demyelinating disease of the central nervous system (CNS).
• Patients with MS experience a range of symptoms, including paresthesia, weakness, and vision problems that vary in presentation (ranging by affected area of the brain/spinal cord).

Skeletal Muscle Structure

• Muscle, fascicle, muscle fiber are components progressively organized in hierarchical fashion in skeletal muscles.
• Muscle fibers contain units called myofibrils, and myofibrils have sarcomeres arranged end-to-end.
• Muscle fibers are composed of myofibrils that are arranged in parallel.
• Myofibrils/sarcomeres are composed of thin (actin) and thick (myosin) filaments.

Myofibrils

• The contractile elements of skeletal muscle.
• Contain contractile proteins (actin and myosin).
• Exhibit a striated appearance.

Sarcomere

• The smallest functional unit of a skeletal muscle fiber.
• Consists of inter-related components (I band, A band, H zone, Z disk and M-line.)
• Actin (thin) and myosin (thick) filaments structure sarcomeres.

Titin

• A large structural protein in sarcomeres that helps stabilize the positions of myosin and actin filaments and acts as a spring which helps return the muscle to its resting length.
• This is important for muscle mechanics and function.
• Plays an important structural role.

Sarcomere: Protein Filaments

• Myosin and actin filaments are crucial parts of the contractile machinery of a muscle fiber.
• Myosin: is the thick filament, comprising about 60% of muscle protein, appears dark, and includes 1500 myosin filaments per myofibril.
• Actin: is the thin filament, comprises about 3000 filaments per myofibril, contains three structural proteins, and appears lighter.
• These proteins interact for muscle contraction to occur.

Myosin (Thick Filaments)

• Each myosin molecule is composed of six polypeptide chains (2 heavy chains, 4 light chains).
• The arrangement of subunits forms twisted filaments with globular heads.
• The heads have sites for interaction with actin and energy expenditure.

Actin (Thin Filaments)

• Actually comprised of multiple proteins (G-actin, tropomyosin, troponin), each with a specific function associated with muscle contraction.
• The actin filament is organized.
• Tropomyosin regulates access to the active site of actin.
• Troponin complex (troponin C, T, I) involved with Ca2+ ions is key to activating the muscle's active sites.

Actin & Myosin Relationship

• Actin and myosin interaction is central for muscle contraction.
• The relationship's dynamic involves proteins, ions, and energy to manage movement.

Sliding Filament Mechanism

• Relaxed state, contracted state, sliding filament mechanism concepts are presented. This is the mechanism of muscle contraction.
• Calcium, ATP, and myosin, and actin interaction are central to the process.
• Energy (ATP) is required to fuel the muscle contraction process.

Skeletal muscle structure: sliding filament mechanism

• The process of muscle contraction, including the role of ATP, calcium, myosin head movement, actin and myosin binding sites, and ATP hydrolysis
• Regulatory proteins to help control the interaction.

The Sliding Filament Model

• Explains how muscle contraction occurs by the interaction of actin and myosin filaments.
• Contraction is achieved by the sliding of actin filaments over the myosin filaments.
• During muscle contraction (or shortening), the I band and H zone shorten. Only the A band remains unchanged.